Respiratory pathology and pathophysiology global overview by Marc Imhotep Cray, M.D.

Marc Imhotep Cray, M.D.

Learning Objectives 1. To list and briefly discuss some of the most important diseases of the respiratory (pulmonary) system 2. To describe the five major disease categories of the respiratory system 3. To understand the most common presenting symptoms & signs suggestive of respiratory disease 4. To introduce the etiologic & pathologic factors, clinical features and treatment approach for select respiratory diseases, including:  Infections  Obstructive Pulmonary Disease  Restrictive Lung Disease  Cystic Fibrosis  Lung Cancer Marc Imhotep Cray, M.D.

Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009 Marc Imhotep Cray, M.D.

Most important diseases of respiratory (pulmonary) system:  Collapse of alveoli (atelectasis) and pneumothorax  Circulatory disturbances, such as pulmonary edema and chronic passive congestion, and adult respiratory distress syndrome (ARDS)  Infections such as rhinitis, laryngitis, bronchitis, and pneumonia  Immunologically mediated diseases, such as asthma  Environmentally induced diseases, such as pneumoconioses, asbestosis, and silicosis  Tumors Marc Imhotep Cray, M.D.

Five Major Pulmonary Disease Categories: 1. Obstructive Pulmonary Diseases (OPDs) 2. Restrictive Lung Diseases (RLDs) 3. Vascular Lung Diseases 4. Pulmonary Infectious Diseases 5. Tumors of the Lung and Pleura

Marc Imhotep Cray, M.D.

Obstructive Pulmonary Diseases (OPDs) ď ą Chronic obstructive pulmonary disease (COPD) is characterized by a reduction of pulmonary air flow as determined by spirometric function tests with normal or increased total lung capacity (TLC), decrease forced vital capacity (FVC) in combination with decreased forced expiratory volume (FEV) ď ą COPD follows either increased resistance to airflow (e.g., by luminal narrowing of air ducts) or loss of elastic recoil (by passive widening of air spaces=increase lung complience)

Marc Imhotep Cray, M.D.

OPDs (2)  COPD can be caused by a number of different respiratory diseases, including:  Emphysema  Chronic bronchitis  Bronchiolitis  Asthma  Cystic fibrosis (CF)  Bronchiectasis or  α1-antitrypsin deficiency  COPD may lead to progressive and destructive emphysema  cor pulmonale  characterized by reduced intrapulmonary blood flow pulmonary hypertension right-sided heart failure Marc Imhotep Cray, M.D.

Restrictive lung diseases (RLDs)  In RLDs lungs have a limited potential to expand thus, compliance is reduced  Although extrapulmonary disorders such as chest abnormalities, intraabdominal masses, and neuromuscular diseases also can limit lung expansion term RLD is generally reserved for intrapulmonary parenchymatous diseases

 Spirometric tests show a reduced FVC with nml or proportionately reduced FEV  RLD occurs in acute and chronic forms  Classic examples of acute RLD are the adult respiratory distress syndrome (ARDS) and acute hypersensitivity pneumonitis  Chronic forms include such pathogenetically different entities as idiopathic pulmonary fibroses (fibrosing alveolitis), chronic interstitial pneumonitis in collagen-vascular diseases, pneumoconioses, and sarcoidosis Marc Imhotep Cray, M.D.

RLDs (2)  Only patients in early stages of acute RLD may recover completely  Later stages and especially chronic forms remit to scarring or progress to extensive interstitial pulmonary fibrosis with honeycombing pulmonary hypertension and development of cor pulmonale  Recurrent superimposed infections further complicate course of RLD  Idiopathic pulmonary fibrosis (A) (repeated cycles of lung injury and wound healing with collagen deposition)

A Marc Imhotep Cray, M.D.

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Obstructive vs. restrictive lung disease

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015) Marc Imhotep Cray, M.D.

Vascular Lung Diseases  Most common vascular lung diseases fall into 2 major categories: 1. clotting disorders with secondary vascular occlusion and 2. primary structural diseases of blood vessels  Clotting disorders may cause occlusion of pulmonary vessels by embolization (DVT to PE) or by in situ thrombosis (e.g., after contraceptive medication with high estrogen content or after clotting disorders in pancreatic carcinoma)  In situ pulmonary thrombosis also may be a consequence of primary structural diseases of lung vasculature

Marc Imhotep Cray, M.D.

Pulmonary Infectious Diseases  Infections of lung present with different pathologic patterns and are classified as:  bacterial pneumonias  atypical and viral pneumonias  Parasitic (e.g., Pneumocystis carinii pneumonia) o yeast-like fungus originally classified as protozoan, now classified as a fungus

 fungal pneumonitis  Most bacterial and viral pneumonias initially are acute inflammatory diseases and, with adequate treatment, may resolve completely  however, pneumonias caused by intracellular bacteria (e.g., Mycobacterium tuberculosis), parasites, or fungi run a protracted and chronic course entailing an immune response and incomplete resolution o heal with focal or diffuse scarring and risk of chronic restrictive pulmonary disease Marc Imhotep Cray, M.D.

Tumors of the Lung and Pleura ď ą As in other organs, tumors of lung are identified as carcinomas (e.g., of bronchial epithelium, bronchial glands, or alveolar lining cells) or as sarcomas (a cancer of connective tissue) ď ą They are classified according to their cell of origin (squamous cell carcinoma [SCC], adenocarcinoma [AC], small-cell carcinoma [oat cell carcinoma]) and to their degree of differentiation ď ą Their local extension and metastatic spread determine their prognosis

Marc Imhotep Cray, M.D.

Tumors of Lung and Pleura (2) ď ą Both tumor classification and documentation of its spread (grading and staging) are important responsibilities of diagnostic pathology and form basis for determining therapeutic intervention ď ą In addition, lungs are frequent sites of metastases from other locations (e.g., breast, pancreas, testes, bone, malignant melanoma of the skin, and others), which must be distinguished from primary lung tumors

Marc Imhotep Cray, M.D.

The Pleura Pneumothorax Pleural Effusion Pleuritis Tumors of the Pleura  Solitary Fibrous Tumor of Pleura  Malignant Mesothelioma

Marc Imhotep Cray, M.D.

Presenting Symptoms Cough  Acute: viral or bacterial bronchitis, URI, TB, drugs or pneumonia  Chronic: asthma, postnasal drip, chronic bronchitis, GERD Hemoptysis  Ask patient to estimate amount of blood  Distinguish between epistaxis, hematemesis, and hemoptysis

Marc Imhotep Cray, M.D.

Presenting Symptoms (2) Dyspnea (difficulty breathing)  Timing, acuity of onset, exacerbating and alleviating factors, degree of functional impairment  Acute (pulmonary embolus) vs chronic (COPD)  Exertional or resting, episodic or continuous  Paroxysmal nocturnal dyspnea (PND)  Orthopnea

Marc Imhotep Cray, M.D.

Presenting Symptoms (3)  What is dyspnea?  difficulty breathing  Shortness of breath  What is orthopnea?  Dyspnea occurring when pt. is in supine position as a result, for example, of a decrease in vital capacity caused by abdominal contents exerting force against diaphragm  What is paroxysmal nocturnal dyspnea (PND)?  Dyspnea occurring several hours after lying down and is often associated with congestive heart failure o It is caused by an increase in venous return to heart resulting in mild pulmonary edema Marc Imhotep Cray, M.D.

Presenting Symptoms (4) Chest pain  Many causes (cardiac, pulmonary, GI, musculoskeletal, etc.)  Pulmonary causes: pleural disease, pulmonary vascular disease, musculoskeletal o lung parenchyma has no pain fibers

 Pleuritic chest pain: sharp or stabbing pain on inspiration that can be positional

Marc Imhotep Cray, M.D.

High-Yield Point: If pain is a symptom also determine the following: – site – radiation – character, e.g. ache, pressure, shooting, stabbing, dull – severity, e.g. ‘Did it interfere with what you were doing? Does it keep you awake?’ – have you ever had this pain before? – is the pain associated with nausea, sweating, e.g. angina?

Presenting Symptoms (5) Evaluation of Pain Use the PQRST mnemonic to improve diagnostic precision  P: provocative and palliative factors  Q: quality  R: region and referral  S: severity  T: timing

Marc Imhotep Cray, M.D.

Other important history Cigarette smoking  Quantified as # of packs smoked/d X # of cumulative years (60pk year = 1 ppd X 60yrs or 2ppd X 30 yrs.)  Risk of lung disease is directly related to # of pack-years exposure and inversely to age at onset of smoking Other environmental exposures (work history), travel  Pneumoconiosis (Silicosis, Coal Worker, Anthracosis)  Asbestosis

Family history (CF, alpha-1 antitrypsin deficiency)

Marc Imhotep Cray, M.D.

Physical Exam* Watch the patient breath RR, use of accessory muscles, paradoxical abdominal breathing, ability to speak in full sentences Shape of patient’s chest cavity   AP diameter suggestive of COPD Auscultation  Rhonchi, rales, wheezing, rub Clubbing *See Pulmonary Physical Examination folder on thumb drive data. Marc Imhotep Cray, M.D.

Signs of acute respiratory failure Signs of acute respiratory failure include:  tachypnea (respiratory rate >40/min)  inability to speak because of dyspnea  accessory muscle use with fatigue despite maximal therapy  confusion  restlessness  agitation  lethargy  a rising PCO2 level  extreme hypoxemia Marc Imhotep Cray, M.D.

Respiratory Infections Upper respiratory infection  Most are viral: common cold, pharyngitis, rhinitis, sinusitis etc. Lower respiratory infection  Frequently viral  Bronchitis (or) asthma: cough, wheezing, dyspnea  Pneumonia: cough, fever, (chills), rapid respiration, dyspnea

Marc Imhotep Cray, M.D.

Case 1 A 68-year-old man presents to the emergency department complaining of a fever, dyspnea, and a cough productive of green sputum. Physical examination reveals an ill-appearing man, breathing heavily. On lung examination, you note bronchial breath sounds and dullness to percussion over the right lower lung lobe. A chest x-ray demonstrates circumscribed opacity over the region of his right lower lung lobe. You obtain sputum and blood cultures and then admit this patient to the hospital for antibiotic treatment.

Marc Imhotep Cray, M.D.

Pneumonia: Overview  Pneumonia is a respiratory disease characterized by inflammation of lung parenchyma (excluding bronchi) caused by viruses, bacteria, fungi, or irritants  General clinical signs and symptoms of pneumonia include:  Fever, chills, muscle stiffness, pleuritic chest pain, cough, blood-tinged or rusty sputum, shortness of breath, rapid heart rate, and difficulty breathing

 Diagnosis is made by several laboratory methods and (or) diagnostic procedures, including:  Chest x-ray; Gram stain and culture (bacterial); bronchoalveolar lavage (Pneumocystis carinii pneumonia [PCP]); serodiagnosis (Mycoplasma)

 Classic laboratory findings associated with bacterial pneumonia are a neutrophilic leukocytosis with an increase in band neutrophils (left shift) Marc Imhotep Cray, M.D.

Pneumonia: Overview (2) ď ąThe four most common bacteria causing sinus and respiratory infections are: 1. Streptococcus pneumoniae 2. Hemophilus influenzae 3. Staphylococcus aureus 4. Mycoplasma pneumoniae ď ąThree common morphologic patterns of pneumonia are: 1. Lobar pneumonia 2. Bronchopneumonia and 3. Interstitial pneumonia Marc Imhotep Cray, M.D.

Pneumonias: Classification

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015) Marc Imhotep Cray, M.D.

Common causes of pneumonia Neonates (< 4 Wks.) Group B streptococci E. coli

Children (4 Wks.–18 Yrs.) Viruses (RSV) Mycoplasma C. trachomatis (infants–3 yr.) C. pneumoniae (school-aged children) S. pneumoniae

Adults (18–40 Yrs.)

Adults (40–65 Yrs.)

Elderly

Mycoplasma C. pneumoniae S. pneumoniae

S. pneumoniae H. influenzae Anaerobes Viruses Mycoplasma

S. pneumoniae Influenza virus Anaerobes H. influenzae Gram-negative rods

Redrawn and modified from: Le T and Bhushan V. First Aid for the USMLE Step 1 2015

Note: Most common pneumonias in childhood are Viral pneumonias Most commonly implicated viruses are Influenza, parainfluenza, respiratory syncytial virus, rhinovirus, and adenovirus Marc Imhotep Cray, M.D.

Common causes of pneumonia (2) Special groups Alcoholic/IV drug user

S. pneumoniae, Klebsiella, S. aureus

Aspiration

Anaerobes (e.g., Peptostreptococcus, Fusobacterium, Prevotella, Bacteroides)

Atypical

Mycoplasma, Legionella, Chlamydia

Cystic fibrosis

Pseudomonas, S. aureus, S. pneumoniae

Immunocompromised

S. aureus, enteric gram-negative rods, fungi, viruses, P. jirovecii (with HIV)

Nosocomial (hospital acquired)

S. aureus, Pseudomonas, other enteric gram-negative rods

Postviral

S. aureus, H. influenzae, S. pneumoniae

Redrawn from: Le T and Bhushan V. First Aid for the USMLE Step 1 2015 Marc Imhotep Cray, M.D.

Lobar Pneumonia ď ą S. pneumoniae most frequently, also Legionella, Klebsiella Intra-alveolar exudateď&#x192; consolidation (A) may involve entire lobe (B) or lung

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Marc Imhotep Cray, M.D.

Bronchopneumonia  S. pneumoniae, S. aureus, H. influenzae, Klebsiella  Acute inflammatory infiltrates (C) from bronchioles into adjacent alveoli  patchy distribution involving ≥ 1 lobe (D)

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015) Marc Imhotep Cray, M.D.

Interstitial (atypical) pneumonia  Viruses (influenza, CMV, RSV, adenoviruses), Mycoplasma, Legionella, Chlamydia  Diffuse patchy inflammation localized to interstitial areas at alveolar walls; diffuse distribution involving ≥ 1 lobe (E)  Generally follows a more indolent course (“walking” pneumonia)

Marc Imhotep Cray, M.D.

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Interstitial & Lobar Pneumonias Compared

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Compare diffuse, patchy bilateral infiltrates of â&#x20AC;&#x153;atypicalâ&#x20AC;? interstitial pneumonia (A) with the localized, dense lesion of lobar pneumonia (B) Marc Imhotep Cray, M.D.

Case 2 A 21-year-old woman presents to the university health clinic complaining of general weakness and a low-grade fever of 3 daysâ&#x20AC;&#x2122; duration. Upon directed history, you learn that she has had an occasional cough and dyspnea and that her two roommates have been suffering from similar symptoms. When a chest x-ray reveals patchy infiltrates, you prescribe her a course of azithromycin and schedule her for a follow-up visit to make sure that her symptoms have resolved.

Marc Imhotep Cray, M.D.

Lung Abscess  Localized collection of pus within parenchyma (A next slide)  Caused by aspiration of oropharyngeal contents (especially in patients predisposed to loss of consciousness [e.g., alcoholics, epileptics]) or bronchial obstruction (e.g., cancer)  Treatment: clindamycin  Air-fluid levels (B next slide) often seen on CXR Fluid levels common in cavities presence suggests cavitation  Due to anaerobes (e.g., Bacteroides, Fusobacterium, Peptostreptococcus) or S. aureus Marc Imhotep Cray, M.D.

Lung Abscess

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Marc Imhotep Cray, M.D.

Case 3 A 42-year-old HIV-positive man presents to the emergency department with hemoptysis. He states that he has lost 15 pounds over the last 2 months and has had an intermittent fever, cough, and chills. He has not been taking any of his HIV medications and his CD4 count is 130. A chest x-ray reveals a lesion in his apical right lung. He is able to cough up green mucous coated with blood. You send the sample off for staining and culture. The sample reveals acid-fast bacilli and you decide to admit this patient to an isolation room and begin him on a multidrug treatment regimen while drug susceptibility tests are run.

Marc Imhotep Cray, M.D.

Pulmonary Tuberculosis  Caused by Mycobacterium tuberculosis  Major global problem; Seen in pts with HIV, other immunocompromised states, developing countries, etc.  Contracted by inhalation

Diagnosis suggested by:  chronic cough  hemoptysis  weight loss  fevers  night sweats

Scanning electron micrograph of

Mycobacterium tuberculosis

M. tuberculosis bacterial colonies Marc Imhotep Cray, M.D.

Pulmonary Tuberculosis (2)

Chandrasoma P, Taylor CR. Concise Pathology, 3rd ed. Stamford, CT: Appleton& Lange, 1998: 523 Marc Imhotep Cray, M.D.

Pulmonary Tuberculosis (3)

Marc Imhotep Cray, M.D.

Pulmonary TB (4) Diagnosis: confirmed by CXR, PPD, sputum smears and culture

Mycobacterium tuberculosis Ziehl-Neelsen stain

 Treatment: 4 drug therapy • Rifampin • Isoniazid • Pyrazinamide • Ethambutol Marc Imhotep Cray, M.D.

Chest X-ray of a person with advanced tuberculosis http://upload.wikimedia.org/wikipedia/commons/ 9/9c/Tuberculosis-x-ray-1.jpg 42

Obstructive Lung Disease: General Obstruction of air flow through airways Major causes:  asthma  bronchiectasis,  emphysema and bronchitis (COPD)  Obstructive lung disease (COPD) Obstruction of air flow resulting in air trapping in lungs Airways close prematurely at high lung volumes, resulting in ↑ RV and ↓ FVC  PFTs: ↓↓ FEV1, ↓ FVC→ ↓↓ FEV1/FVC ratio (hallmark)  V/Q mismatch Marc Imhotep Cray, M.D.

Pathophysiology of Obstructive Lung Disease Air flow is decreased by: airway narrowing and/or loss of elastic recoil of the lung Airway Narrowing  Airway inflammation otobacco smoke, recurrent infection, immunologic dysfunction  Bronchoconstriction

Marc Imhotep Cray, M.D.

Pathophysiology (2) Loss of elastic recoil  COPD: loss of airway tone and decreased tethering by surrounding lung  Asthma: bronchoconstriction and mucus plugging allowing airways to collapse at higher lung volumes and trap excessive air  Increased ventilation: increased airflow resistance may not allow lungs to completely empty during expiration

Marc Imhotep Cray, M.D.

Chronic Obstructive Lung Disease (COPD) Slowly progressive, irreversible airway obstruction  Again, it is closely linked to smoking Exacerbations of disease by bacterial/viral infections, heart failure, medication non-compliance, etc. Characterized by dyspnea, sputum production (with chronic bronchitis)

Marc Imhotep Cray, M.D.

COPD: types Chronic bronchitis (defined clinically)  persistent cough with sputum production for at least 3 months over 2 or more consecutive years Emphysema (defined based on pathologic findings)  abnormal enlargement of air spaces  permanently dilated airways distal to terminal bronchioles with alveolar destruction and bullae formation  degree of obstruction in patients with COPD correlates more closely with severity of emphysema Marc Imhotep Cray, M.D.

Schematic representation of overlap between chronic obstructive lung diseases:

Marc Imhotep Cray, M.D.

Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th ed. 2014

Marc Imhotep Cray, M.D.

Case 4 A 44-year-old man presents to your office complaining of a persistent cough, which is productive of copious sputum. He admits that he is a heavy smoker and has suffered from similar coughs for several years. Physical examination reveals diffuse wheezing and crackles. You suspect that this patient will have a decreased FEV1/FVC ratio and strongly suggest that he stop smoking.

Marc Imhotep Cray, M.D.

Bronchitis Chronic bronchitis (“blue bloater”) Pathology  Hyperplasia of mucus-secreting glands in bronchi Reid index (thickness of gland layer/total thickness of bronchial wall) > 50%. Features  Productive cough for > 3 months per year (not necessarily consecutive) for 2 or more years  Findings: wheezing, crackles, cyanosis (early onset hypoxemia due to shunting), late-onset dyspnea, CO2 retention (hypercapnia), 2° polycythemia Marc Imhotep Cray, M.D.

Case 5 A63-year-old man presents to your office complaining of worsening shortness of breath over the past year. You know that this patient has smoked two packs of cigarettes a day for the past 45 years. As you are talking to the patient, you notice that he is using his accessory muscles of respiration to breathe, that his chest is barrel shaped and that he is breathing carefully through pursed lips. Using a spirometer, you determine that he has a decreased FEV1/FVC ratio and an increased TLC. You tell the patient that it is imperative that he stop smoking and prescribe him a tiotropium inhaler.

Marc Imhotep Cray, M.D.

Emphysema Emphysema (“pink puffer”) Pathology  Enlargement of air spaces, dec. recoil, inc. compliance, dec. diffusing capacity for CO resulting from destruction of alveolar walls (arrow in A )

Marc Imhotep Cray, M.D.

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Emphysema (2) Two types: Centriacinarâ&#x20AC;&#x201D;associated with smoking (B, C)

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Marc Imhotep Cray, M.D.

Emphysema (3) Panacinar—associated with α 1-protease (α 1-antitrypsin) inhibitor deficiency Features  Inc. elastase activity  loss of elastic fibers inc. lung compliance  Exhalation through pursed lips to inc. airway pressure and prevent airway collapse during respiration D  Barrel-shaped chest (D) High-Yield Tip: Alpha 1 protease inhibitor is capable of inhibiting several types of proteases, including neutrophil elastase, which is implicated in the genesis of emphysema Marc Imhotep Cray, M.D.

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

COPD Physical Exam   AP diameter,  RR Laboratory data;  Pulmonary function test is sensitive way to make diagnosis in early stages  ABG: hypoxia, hypercarbia (advanced)  CXR: hyperinflation, flattened diaphragms, increased AP diameter, widened retrosternal air space (with emphysema)

Marc Imhotep Cray, M.D.

COPD: Hyperinflation

Marc Imhotep Cray, M.D.

COPD: flattened diaphragms, lucency

Marc Imhotep Cray, M.D.

COPD Treatment  STOP smoking (if this is cause)  Treat exacerbations of bronchitis with antibiotics  Most meds have not been found to be helpful  Ipratropium bromide MDI (atrovent MDI) is helpful (anticholinergic)  Steroids not usually helpful unless inflammatory component

Marc Imhotep Cray, M.D.

Case 6 A 25-year-old man presents to the emergency department with hemoptysis associated with a chronic productive cough. He reports suffering from chronic sinusitis and has had several bouts of severe pneumonia that have required hospitalization in the past. Pulmonary function tests reveal a decreased FEV1/FVC ratio. When CT scan reveals dilated bronchioles with signet-ring appearance, you decide to check for situs inversus because his present condition may be associated with a rare genetic disorder.

Marc Imhotep Cray, M.D.

Bronchiectasis  Etiology Caused by bronchial obstruction (tumor, foreign body, mucus), chronic necrotizing infections of bronchi, or cystic fibrosis  Pathology Lung: Dilated airways usually in lower lobes; inflammation within bronchial walls; fibrosis of bronchial walls in chronic disease  Clinical Manifestations Chronic cough with copious purulent sputum; hemoptysis; cyanosis; anemia  Complications include lung and brain abscesses or cor pulmonale  Imaging: Dilated bronchioles with signet-ring appearance on CT scan  Lab findings: Decreased FEV1/FVC ratio, decreased Hct  Treatment Antibiotics; bronchodilators; surgical resection for localized disease High-Yield Note: Kartagener syndrome is caused by a defect in dynein, leading to immotile cilia. Clinical manifestations include bronchiectasis, sterility, recurrent sinusitis, and situs inversus (dextrocardia) Marc Imhotep Cray, M.D.

Case 7 An 8-year-old girl is brought into an urgent-care clinic complaining of shortness of breath. Her past medical history is significant for multiple allergies. Upon physical examination, you hear expiratory wheezes and you observe that the patient is using her accessory muscles of respiration. You decide to administer an inhaled Î˛2adrenergic agonist for relief of her symptoms.

Marc Imhotep Cray, M.D.

Asthma Hypersensitivity of bronchial airways results in symptomatic bronchospasm  Can be triggered by viral URIs, allergens, stress

Obstruction of lumen of bronchiole by mucoid exudate, goblet cell metaplasia, epithelial basement membrane thickening and severe inflammation of bronchiole in a patient with asthma

 Test with methacholine challenge  Findings: cough, wheezing, tachypnea, dyspnea, hypoxemia, inspiratory/expiratory ratio, pulsus paradoxus, mucus plugging Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015 Marc Imhotep Cray, M.D.

Asthma (2) Pathology: ď ą Bronchial hyperresponsiveness causes reversible bronchoconstriction ď ą Smooth muscle hypertrophy, Curschmann spirals (shed epithelium forms whorled [A] ) , and Charcot-Leyden crystals (eosinophilic, hexagonal, double-pointed, needle-like crystals formed from breakdown of eosinophils in sputum) mucus plugging [B]

[A]

[B] Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015

Marc Imhotep Cray, M.D.

Asthma (3)  Chronic, inflammatory disorder of airways  3-5% of the population is affected  Imbalance between proinflammatory and inhibitory cytokines  Episodic airway narrowing, increased airway reactivity, and reversibility

Marc Imhotep Cray, M.D.

Asthma (4) Trigger: extrinsic allergens, intrinsic factors, or no identifiable cause Types: extrinsic, intrinsic, exercise induced, ASA (acetyl salicylic acid) sensitive, occupational, allergic bronchopulmonary aspergillosis (ABPA) Precipitants of asthma: postnasal drip, GERD, cold exposure, gases/fumes, emotional stress, hormones, resp. infections

Marc Imhotep Cray, M.D.

Asthma (5) Diagnosis (one or combination):  wheeze, chronic episodic dyspnea, and chronic cough  Sputum production, chest pain or tightness Testing:  History, CXR (to rule out other causes), pulmonary function testing (with or without methacholine challenge)

Marc Imhotep Cray, M.D.

Asthma (6) Treatment  Education (removal of offending agents)  Peak flow meters  Inhaled corticosteroids (ex. fluticasone)  Long and short acting bronchodilators oEx. salmeterol, albuterol  Leukotriene inhibitors (ex. montelukast)  Theophylline (limited use today due to potential toxicity)

Marc Imhotep Cray, M.D.

Case 8 A 2-year-old girl is brought to the emergency department because of shortness of breath and a productive cough. Upon questioning her parents, you discover that this patient has a history of pulmonary infections and bulky stools that float. Physical examination reveals a thin girl with a barrel-shaped chest, crackles over both lungs, and digital clubbing. Later, a sweat test demonstrates high levels of chloride ions. You realize that this girl will have a severely shortened life span owing to her condition.

Marc Imhotep Cray, M.D.

Cystic Fibrosis  An Obstructive Lung Disease Autosomal recessive genetic disorder

Affects Pulm, GI and GU systems Most common lethal genetic disorder  1/25 carrier frequency  1/3200 live births affected

Marc Imhotep Cray, M.D.

A breathing treatment for cystic fibrosis, using a mask nebulizer and a ThAIRapy Vest http://en.wikipedia.org/wiki/File:CFtreatmentvest2.JPG

Cystic Fibrosis (2) Abnormal chloride channel leads to thick and viscous secretions in resp, hepatobiliary, GI, and reproductive tracts Resp tract: persistent inflammation and infection causes bronchial wall destruction; mucus plugging of small airways causing parenchymal destruction • colonization by S. aureus, H. influenza, P. aeruginosa

Marc Imhotep Cray, M.D.

Cystic Fibrosis (3) Testing:  Chloride sweat test  Genetic testing Median survival  14 years in 1969 to  30 yrs. since 1995

Marc Imhotep Cray, M.D.

Cystic Fibrosis (4) Pathology:  Pulmonary: cough, sputum production, clubbing  Upper Resp tract: nasal polyps, sinusitis  GI: exocrine pancreatic dysfunction, diabetes, cirrhosis, salivary gland inflammation  GU: azoospermia, decreased fertility rate in women, nephrolithiasis

Marc Imhotep Cray, M.D.

Cystic Fibrosis Summary Mutation: Cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7 Epidemiology: 1 in 3500 live births; whites predominantly; uncommon in Asians and African Americans

Mechanism: Impaired resorption of chloride from lumen of sweat ducts resultant impaired absorption of sodium impaired secretion of chloride into airways, pancreatic ducts, and gastrointestinal tract resulting in less secretion of sodium and water and, therefore, viscid secretions Marc Imhotep Cray, M.D.

Cystic Fibrosis Summary (2) Manifestations of cystic fibrosis  Fibrosis of pancreas  Recurrent pulmonary infections with Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia  Chronic bronchitis, bronchiectasis  Meconium ileus  Biliary cirrhosis leading to impaired absorption of the fat soluble vitamins A, D, E, and K  Infertility in males secondary to absence of vas deferens

Laboratory studies: Increased concentration of chloride in sweat (i.e., positive sweat chloride test) Marc Imhotep Cray, M.D.

Marc Imhotep Cray, M.D.

http://en.wikipedia.org/wiki/Cystic_fibrosis

CF Treatment  Aggressive airway hygiene  Nutritional support including pancreatic enzyme replacement  Antibiotics  Bronchodilators

Marc Imhotep Cray, M.D.

Case 9 A 49-year-old man presents to your clinic complaining of mild shortness of breath over the past year. He does not smoke, although he has worked in a glass-manufacturing factory for over 20 years. A chest x-ray reveals eggshell calcification of the hilar lymph nodes. You make a diagnosis and suggest that he have a PPD placed because his condition is associated with increased susceptibility to tuberculosis.

Marc Imhotep Cray, M.D.

Restrictive lung disease (Interstitial lung disease [ILD])  Many pulmonary disorders are characterized by interstitial inflammatory infiltrates and have similar clinical and radiologic presentations  grouped as interstitial, infiltrative or restrictive diseases  may (1) be acute or chronic, (2) be of known or unknown etiology and (3) vary from minimally symptomatic to severely incapacitating and lethal interstitial fibrosis  Restrictive lung diseases are characterized by decreased lung volume and decreased oxygen diffusing capacity on pulmonary function studies

Marc Imhotep Cray, M.D.

Restrictive lung disease (2)  Restricted lung expansion causes ↓ lung volumes (↓ FVC and TLC) PFTs FEV1/FVC ratio > 80%.  Types: 1. Poor breathing mechanics (extrapulmonary, peripheral hypoventilation): a. Poor muscular effort polio, myasthenia gravis b. Poor structural apparatus scoliosis, morbid obesity

Marc Imhotep Cray, M.D.

Restrictive lung disease (3) 2. Interstitial lung diseases (pulmonary, lowered diffusing capacity): a. b. c. d. e.

Adult respiratory distress syndrome (ARDS) Neonatal respiratory distress syndrome (hyaline membrane disease) Pneumoconioses (coal miner’s silicosis, asbestosis) Sarcoidosis Idiopathic pulmonary fibrosis (repeated cycles of lung injury and wound healing with ↑ collagen) f. Goodpasture’s syndrome g. Wegener’s granulomatosis h. Eosinophilic granuloma (histiocytosis X) i. Drug toxicity (bleomycin, busulfan, amiodarone)

Marc Imhotep Cray, M.D.

Case 10 A 63-year-old man presents to your office after noticing that his left eyelid is droopy. Upon further questioning, he admits to some shortness of breath over the past 2 months, but attributes that to his 40-year-long heavy smoking habit. Physical examination reveals ptosis and miosis of the left eye and extremely dry skin of the left face. A chest x-ray demonstrates an irregular mass in the apex of his left lung. You admit the patient to the hospital for a biopsy of the mass, but you fear that the prognosis is not good.

Marc Imhotep Cray, M.D.

Lung Cancer  Lung cancer is a leading cause of cancer death  Presentation: cough, hemoptysis, bronchial obstruction, wheezing, pneumonic “coin” lesion on x-ray film Squamous cell carcinoma in the right lower lobe First Aid

for the USMLE Step 1 2008

Marc Imhotep Cray, M.D.

Lung Cancer (2) Risk Factors  Leading cause of death  Cigarette smoking is responsible for >90% of lung cancers  Risk increases with dose and length of exposure to cigarette smoking  Heavy occupational exposure to asbestos is second most important cause

Marc Imhotep Cray, M.D.

Lung Cancer: Types  Bronchial carcinoid tumors  Small cell cancer (oat cell carcinoma, assoc. with smoking)  Non-small cell cancer oSquamous cell cancer (assoc. with smoking) oAdenocarcinoma oLarge cell Note: oAnaplastic carcinoma  Oat cell is a neoplasm of neuroendocrine  Metastasis: breast, liver, renal, colon Kulchitsky cells  Non small cell carcinomas (NSCC) are any  Pleural Ca epithelial derived lung cancers that are not small cell carcinoma (SCC) oMesothelioma o They are relatively insensitive to • associated with asbestosis

Marc Imhotep Cray, M.D.

chemotherapy 85

Lung Cancer: Types (2)

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015 Marc Imhotep Cray, M.D.

Lung Cancer: Clinical Presentation Symptoms can be quite non-specific Symptoms may relate to location and size of tumor  Cough, hemoptysis, post-obstructive pneumonia, chest pain, wheezing, hoarseness  bone metastases: swelling, pain  hepatic metastases: jaundice, hepatomegaly  weight loss, anorexia

Marc Imhotep Cray, M.D.

Lung Cancer: Evaluation  History and physical examination  CXR/CT scan  No lab is helpful  Bronchoscopy  VATS (video-assisted thoracic surgery)

Marc Imhotep Cray, M.D.

Lung Cancer: Treatment  Options depend on tumor type, size, stage of disease, and performance status of the pt.  Surgical removal with Stage I, II, IIIA non-small cell cancer (if operable)  Chemotherapy with radiation for limited stage disease in small cell cancer ofrequent metastases to the brain

Marc Imhotep Cray, M.D.

Lung Cancer: Survival ď&#x201A;§ 15-25% survival 5 years after the diagnosis ď&#x201A;§ Considerable debate about screening for lung cancer orecent discussion on chest C.T. as screening tool oCXR is not a sensitive way to screen for cancer

Marc Imhotep Cray, M.D.

Further study: eLearning: IVMS General and Systems Pathology Cloud Folder IVMS Respiratory Module Cloud Folder Internet Pathology Laboratory for Medical Education Pulmonary Pathology Each section consists of a series of images demonstrating gross and microscopic pathologic findings for a variety of disease processes. A short description accompanies each image. http://library.med.utah.edu/WebPath/webpath.html#MENU Textbooks: Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th ed. Philadelphia: Saunders, 2014 Rubin R and Strayer DS Eds. Rubinâ&#x20AC;&#x2122;s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012 Marc Imhotep Cray, M.D.

e-Medicine (Medscape) Articles Obstructive Airway Diseases  Alpha1-Antitrypsin Deficiency  Asthma  Bronchiectasis  Bronchiolitis  Bronchitis  Chronic Bronchitis  Chronic Obstructive Pulmonary Disease  Emphysema  Status Asthmaticus Marc Imhotep Cray, M.D.